EP0630259B1 - Mycobacterium vaccae utilise dans le traitement d'affections auto-immunes de longue duree - Google Patents

Mycobacterium vaccae utilise dans le traitement d'affections auto-immunes de longue duree Download PDF

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Publication number
EP0630259B1
EP0630259B1 EP93905460A EP93905460A EP0630259B1 EP 0630259 B1 EP0630259 B1 EP 0630259B1 EP 93905460 A EP93905460 A EP 93905460A EP 93905460 A EP93905460 A EP 93905460A EP 0630259 B1 EP0630259 B1 EP 0630259B1
Authority
EP
European Patent Office
Prior art keywords
vaccae
treatment
use according
infection
antigenic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP93905460A
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German (de)
English (en)
Other versions
EP0630259A1 (fr
Inventor
John Lawson Stanford
Graham Arthur William Rook
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Silence Therapeutics PLC
Original Assignee
University College London
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Filing date
Publication date
Application filed by University College London filed Critical University College London
Priority to EP96201912A priority Critical patent/EP0763361B1/fr
Publication of EP0630259A1 publication Critical patent/EP0630259A1/fr
Application granted granted Critical
Publication of EP0630259B1 publication Critical patent/EP0630259B1/fr
Priority to GR20000401468T priority patent/GR3033772T3/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to the treatment of mental diseases associated with an autoimmune reaction which may have been initiated by an infection.
  • immunotherapeutic agents comprising killed cells of Mycobacterium vaccae. These agents are useful in the immunotherapy of mycobacterial disease, especially tuberculosis and leprosy. It is stated that use of this immunotherapeutic agent facilitates the removal of the persisting bacilli responsible for tuberculosis or leprosy which, as is well known, it is difficult to remove by chemotherapy alone. It is suggested in the specification that the immunotherapeutic agent is believed to act by presenting the "protective" common mycobacterial antigens to advantage and by containing immune suppressor determinants which are active in regulating disadvantageous immune mechanisms. As a consequence, "persister" bacilli are recognised by the immune system by their content of common mycobacterial antigens and effective immune mechanisms are directed against them, in the absence of the tissue necrotic form of immunity usually present in mycobacterial disease.
  • compositions which comprise M. vaccae as active ingredient are useful in the treatment of other pathological conditions in which the patient shows an abnormally high proportion of agalactosyl IgG and also in the treatment of chronic inflammatory disorders caused or accompanied by an abnormally high release by macrophages of interleukin-6 and/or tumour necrosis factor.
  • the specification refers in particular to the treatment of Crohn's disease, reactive arthritis, primary biliary cirrhosis, sarcoidosis, ulcerative colitis, psoriasis, systemic lupus erythematosus (especially when accompanied by Sjogren's syndrome), multiple sclerosis, Guillain-Barre syndrome, primary diabetes mellitus, and some aspects of graft rejection.
  • the present invention is based on the surprising observation that M. vaccae is also effective against a number of other conditions which may involve infections such as bacterial or protozoan infections and in particular mycobacterial infections.
  • M. vaccae is effective in the treatment of the immunologically mediated consequences of chronic infections.
  • Chaga's disease (South American Trypanosomiasis) is an example of a disease associated with a protozoan infection a late consequence of which is myocarditis which normally leads to the death of a patient. Treatment with M. vaccae may reduce the incidence of myocarditis.
  • Takayasu's arteritis which is associated with tuberculosis which is caused by mycobacterial infection. It is believed that this and other vascular diseases including obstructive vascular diseases, which may be immunologically mediated, may be prevented and treated with M. vaccae .
  • M. vaccae may be effective in the prophylaxis and treatment of vascular complications associated with diabetes, which may be immunologically mediated.
  • the invention provides antigenic and immunoregulatory material derived from M. vaccae for use in the manufacture of a therapeutic agent for the treatment of a mental disease associated with an autoimmune reaction which may have been initiated by an infection.
  • the present invention is in particular directed to treatment of bacterial or protozoan infections, for example mycobacterial infections.
  • the antigenic or immunoregulatory material is for use in the treatment of a mental disease associated with an autoimmune reaction initiated by an infection, such as a mycobacterial infection.
  • an infection such as a mycobacterial infection.
  • an infection may be a past infection which triggers an autoimmune response.
  • the autoimmune response may be initiated by an ongoing infection, such as a mycobacterial infection, which is cryptic, i.e. not readily detectable.
  • the therapeutic agent conveniently, and therefore preferably, comprises dead cells of M. vaccae , most preferably cells which have been killed by autoclaving or by irradiation.
  • the therapeutic agent normally comprises more than 10 8 microorganisms per ml of diluent, and preferably from 10 8 to 10 11 killed M. vaccae microorganisms per ml of diluent.
  • the diluent may be pyrogen-free saline for injection alone, or a borate buffer of pH8.0.
  • the diluent should be sterile.
  • a suitable borate buffer is:
  • the preferred strain of M. vaccae is one denoted R877R isolated from mud samples from the Lango district of Central Kenya (J.L. Stanford and R.C. Paul, Ann. Soc. Belge Med, Trop. 1973, 53 141-389).
  • the strain is a stable rough variant and belongs to the aurum sub-species. It can be identified as belonging to M. vaccae by biochemical and antigenic criteria (R. Bonicke, S.E. Juhasz., Zentr albl. Bakteriol. Parasitenkd. Infection skr. Hyg. Abt. 1, Orig., 1964, 192 , 133.
  • the strain denoted R877R has been deposited under the Budapest Convention at the National Collection of Type Cultures (NCTC) Central Public Health Laboratory, Colindale Avenue, London NW9 5HT, United Kingdom on February 13th, 1984 under the number NCTC 11659.
  • the microorganism M. vaccae may be grown on a suitable solid medium.
  • a modified Sauton's liquid medium is preferred (S.V. Boyden and E. Sorkin., J. Immuno, 1955 75 , 15) solidified with agar.
  • the solid medium contains 1.3% agar.
  • the medium inoculated with the microorganisms is incubated aerobically to enable growth of the microorganisms to take place, generally at 32°C for 28 days.
  • the organisms are harvested, then weighed and suspended in a diluent.
  • the diluent may be unbuffered saline but is preferably borate-buffered and contains a surfactant such as Tween 80 as described above.
  • the suspension is diluted to give 100mg of microorganism/ml.
  • borate buffered saline is preferably used so that the suspension contains 10 mg wet weight of microorganisms/ml in multidose vials.
  • the microorganisms in the vials may be killed using irradiation e.g. from 60 Cobalt at a dose of 2.5 megarads, or by any other means, for example chemically, it is preferred to kill the microorganisms by autoclaving, for example at 15 psi (103.5 kPa) for 15 minutes (115°-125°C). It has been discovered that autoclaving yields a more effective preparation than irradiation.
  • the therapeutic agent is in general administered by injection in a volume in the range 0.1-0.2 ml, preferably 0.1ml given intradermally.
  • a single dosage will generally contain from 10 7 to 10 10 killed M. vaccae microorganisms. It is preferred to administer to patients a single dose containing 10 8 to 10 9 killed M. vaccae .
  • a single dose may be administered or the dose may be repeated depending on the condition of the patient.
  • the therapeutic agent will generally be administered by intradermal injection, other routes, e.g. oral administration, can also be used.
  • M. vaccae it may be advantageous and is within the scope of the invention to use more than one strain of M. vaccae , and/or to include in the antigenic on immunoregulatory material other closely related mycobacterial species, such as M. nonchromogenicum or M. chitae . Tuberculin may also be included.
  • the therapeutic agent can contain further ingredients such as adjuvants, preservatives, stabilisers etc. It may be supplied in sterile injectable liquid form or in sterile freeze-dried form which is reconstituted prior to use.
  • M. vaccae may be used as such or an extract or fractioned portion of the organism to manufacture the therapeutic agents according to the invention.
  • M. vaccae NCTC 11659 is grown on a solid medium comprising modified Sauton's medium solidified with 1.3% agar.
  • the medium is inoculated with the microorganism and incubated for 28 days at 32°C to enable growth and maturation of the microorganism to take place.
  • the microorganisms are then harvested by gently scraping the surface of the agar and weighed (without drying) and suspended in M/15 borate buffered saline at pH8 to give 10 mg of microorganisms/ml of saline.
  • the suspension is dispensed into 5 ml vials, and then autoclaved for 15 minutes at 15 psi (103.5 kPa) to kill the microorganisms.
  • a single dose consists of 0.1ml of the suspension, which should be shaken vigorously immediately before use, containing 1 mg wet weight of M. vaccae .
  • the dose is given by intradermal injection normally over the left deltoid muscle.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • External Artificial Organs (AREA)
  • Soil Working Implements (AREA)
  • Storage Of Fruits Or Vegetables (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Saccharide Compounds (AREA)

Claims (6)

  1. Utilisation de matériel antigénique et/ou immunorégulateur provenant de Mycobacterium vaccae dans la préparation d'un agent thérapeutique destiné au traitement d'une maladie mentale associée à une réaction auto-immune susceptible d'avoir été déclenchée par une infection.
  2. Utilisation selon la revendication 1, dans laquelle la maladie mentale est associée à une réaction auto-immune déclenchée par une infection.
  3. Utilisation selon la revendication 1 ou 2, dans laquelle le matériel antigénique et/ou immunorégulateur provenant de M. vaccae comprend des cellules mortes de M. vaccae.
  4. Utilisation selon la revendication 3, dans laquelle les cellules de M. vaccae ont été tuées par passage à l'autoclave.
  5. Utilisation selon l'une quelconque des revendications précédentes, dans laquelle le matériel provenant de M. vaccae provient de la souche telle que déposée auprès du National Collection of Type Cultures (NCTC) Central Public Health Laboratory, Colindale Avenue, Londres NW9 5HT, Royaume-Uni, le 13 février 1984 sous le numéro NCTC 11659.
  6. Utilisation selon l'une quelconque des revendications précédentes, dans laquelle l'agent thérapeutique contient, par dose, le matériel antigénique et/ou immunorégulateur de 107 à 1010 micro-organismes M. vaccae.
EP93905460A 1992-02-21 1993-02-19 Mycobacterium vaccae utilise dans le traitement d'affections auto-immunes de longue duree Expired - Lifetime EP0630259B1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP96201912A EP0763361B1 (fr) 1992-02-21 1993-02-19 Mycobactérium vaccae pour traiter des conditions autoimmunes à longes termes
GR20000401468T GR3033772T3 (en) 1992-02-21 2000-06-23 Mycobacterium vaccae for treatment of long term autoimmune conditions

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB929203814A GB9203814D0 (en) 1992-02-21 1992-02-21 Treatment of long term auto-immune conditions
GB9203814 1992-02-21
PCT/GB1993/000351 WO1993016727A1 (fr) 1992-02-21 1993-02-19 Mycobacterium vaccae utilise dans le traitement d'affections auto-immunes de longue duree

Related Child Applications (2)

Application Number Title Priority Date Filing Date
EP96201912A Division EP0763361B1 (fr) 1992-02-21 1993-02-19 Mycobactérium vaccae pour traiter des conditions autoimmunes à longes termes
EP96201912.1 Division-Into 1996-07-08

Publications (2)

Publication Number Publication Date
EP0630259A1 EP0630259A1 (fr) 1994-12-28
EP0630259B1 true EP0630259B1 (fr) 1997-04-16

Family

ID=10710862

Family Applications (2)

Application Number Title Priority Date Filing Date
EP96201912A Expired - Lifetime EP0763361B1 (fr) 1992-02-21 1993-02-19 Mycobactérium vaccae pour traiter des conditions autoimmunes à longes termes
EP93905460A Expired - Lifetime EP0630259B1 (fr) 1992-02-21 1993-02-19 Mycobacterium vaccae utilise dans le traitement d'affections auto-immunes de longue duree

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP96201912A Expired - Lifetime EP0763361B1 (fr) 1992-02-21 1993-02-19 Mycobactérium vaccae pour traiter des conditions autoimmunes à longes termes

Country Status (24)

Country Link
US (1) US5885588A (fr)
EP (2) EP0763361B1 (fr)
JP (1) JPH07506093A (fr)
KR (1) KR100275862B1 (fr)
AT (2) ATE192046T1 (fr)
AU (2) AU675421B2 (fr)
BG (1) BG99054A (fr)
BR (1) BR9305946A (fr)
CA (1) CA2130117A1 (fr)
CZ (1) CZ282651B6 (fr)
DE (2) DE69309915T2 (fr)
DK (2) DK0630259T3 (fr)
ES (2) ES2145968T3 (fr)
FI (1) FI943849A0 (fr)
GB (1) GB9203814D0 (fr)
GR (2) GR3024113T3 (fr)
HU (1) HU218347B (fr)
NO (1) NO311169B1 (fr)
NZ (1) NZ249518A (fr)
RO (1) RO117833B1 (fr)
RU (1) RU2124367C1 (fr)
SK (1) SK99994A3 (fr)
UA (1) UA35583C2 (fr)
WO (1) WO1993016727A1 (fr)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9406301D0 (en) * 1994-03-30 1994-05-25 Univ London Immunotherapeutic agent and its use
IL110011A (en) * 1994-06-13 2004-09-27 Yeda Res & Dev Pharmacological preparations for the treatment of schizophrenia
GB9505658D0 (en) * 1995-03-21 1995-05-10 Univ London Hormone and growth factor mimetics
US6056964A (en) * 1995-03-29 2000-05-02 Stanford Rook Limited Immunotherapeutic agent and its use
AU741016B2 (en) * 1996-08-29 2001-11-22 Genesis Research And Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
US6406704B1 (en) 1996-08-29 2002-06-18 Genesis Research And Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
US6284255B1 (en) * 1996-08-29 2001-09-04 Genesis Research & Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
US5985287A (en) * 1996-08-29 1999-11-16 Genesis Research And Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
US6160093A (en) * 1996-08-29 2000-12-12 Genesis Researth And Development Corporation Limited Compounds and methods for treatment and diagnosis of mycobacterial infections
DE69734461T2 (de) * 1996-12-18 2006-07-06 Stanford Rook Ltd. Verwendung von mycobacterium vaccae zur therapie des chronischen müdigkeitssyndrom
US6878377B2 (en) 1996-12-18 2005-04-12 Stanford Rook Limited Mycobacterium vaccae for down-regulation of the Th2 activity of the immune system
BR9814432A (pt) * 1997-12-23 2000-10-10 Genesis Res & Dev Corp Ltd Composições derivadas de mycobacterium vaccae e processo para seu uso
US6328978B1 (en) 1997-12-23 2001-12-11 Genesis Research & Development Corp. Ltd. Methods for the treatment of immunologically-mediated skin disorders
US5968524A (en) * 1997-12-23 1999-10-19 Genesis Research & Development Corp. Methods and compounds for the treatment of immunologically-mediated psoriasis
US6350457B1 (en) 1999-06-02 2002-02-26 Genesis Research & Development Corporation Limited Methods and compounds for the treatment of immunologically-mediated diseases using mycobacterium vaccae
WO2001010221A1 (fr) * 1999-08-06 2001-02-15 Corixa Corporation Vaccins pour le traitement de maladies auto-immunes
GB0010496D0 (en) * 2000-04-28 2000-06-14 Stanford Rook Ltd Treatment of conditions of the central nervous system
GB0106985D0 (en) * 2001-03-20 2001-05-09 Stanford Rook Ltd Immunotherapeutic agent
GB0106986D0 (en) * 2001-03-20 2001-05-09 Stanford Rook Ltd Immunotherapeutic agent
JP4875494B2 (ja) * 2003-11-14 2012-02-15 ユーシーエル バイオメディカ ピーエルシー 免疫調節物質

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8404280D0 (en) * 1984-02-17 1984-03-21 Stanford J L Biological preparations
IL71683A0 (en) * 1984-04-27 1984-09-30 Yeda Res & Dev Pharmaceutical compositions for treating arthritis type diseases comprising fractions obtained from mycobacteria
GB8919321D0 (en) * 1989-08-25 1989-10-11 Univ London Treatment of chronic inflammatory conditions
AU660430B2 (en) * 1990-11-08 1995-06-29 Stanford Rook Limited Mycobacterium as adjuvant for antigens

Also Published As

Publication number Publication date
GR3024113T3 (en) 1997-10-31
DK0630259T3 (da) 1997-09-15
FI943849A0 (fi) 1994-08-22
BG99054A (en) 1995-08-28
US5885588A (en) 1999-03-23
HU9402422D0 (en) 1994-10-28
DK0763361T3 (da) 2000-08-07
CZ282651B6 (cs) 1997-08-13
NO311169B1 (no) 2001-10-22
EP0763361B1 (fr) 2000-04-26
AU675421B2 (en) 1997-02-06
AU7188796A (en) 1997-02-06
JPH07506093A (ja) 1995-07-06
ATE192046T1 (de) 2000-05-15
DE69328503T2 (de) 2000-08-24
KR100275862B1 (ko) 2000-12-15
RU94045825A (ru) 1997-02-20
AU3637793A (en) 1993-09-13
KR950700755A (ko) 1995-02-20
NO943082D0 (no) 1994-08-22
DE69309915T2 (de) 1997-07-24
HUT69941A (en) 1995-09-28
CA2130117A1 (fr) 1993-09-02
WO1993016727A1 (fr) 1993-09-02
AU706122B2 (en) 1999-06-10
RO117833B1 (ro) 2002-08-30
DE69328503D1 (de) 2000-05-31
CZ202394A3 (en) 1995-02-15
SK99994A3 (en) 1995-05-10
GR3033772T3 (en) 2000-10-31
ES2104131T3 (es) 1997-10-01
GB9203814D0 (en) 1992-04-08
HU218347B (hu) 2000-08-28
EP0763361A2 (fr) 1997-03-19
EP0763361A3 (fr) 1997-03-26
ATE151641T1 (de) 1997-05-15
NZ249518A (en) 1997-07-27
RU2124367C1 (ru) 1999-01-10
BR9305946A (pt) 1997-10-21
UA35583C2 (uk) 2001-04-16
EP0630259A1 (fr) 1994-12-28
NO943082L (no) 1994-10-17
ES2145968T3 (es) 2000-07-16
DE69309915D1 (de) 1997-05-22

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